Analysis of Dyes in Cosmetics: Challenges and Recent Developments

cosmetics

Review Analysis of Dyes in Cosmetics: Challenges and Recent Developments

Eugenia Guerra, Maria Llompart ID and Carmen Garcia-Jares * Laboratory of Research and Development of Analytical Solutions (LIDSA), Department of Analytical Chemistry, Nutrition and Food Science, Faculty of Chemistry, Universidade de Santiago de Compostela, E-15782 Santiago de Compostela, Spain; [email protected] (E.G.); [email protected] (M.L.) * Correspondence: [email protected]; Tel.: +34-8818-14394

Received: 4 July 2018; Accepted: 20 July 2018; Published: 23 July 2018

Abstract: Colour plays a decisive role in the marketing of a cosmetic product. Among thousands of substances used to colour, synthetic dyes are the most widespread in the industry. Their potential secondary effects on human health and different regulatory requirements for their use between the main world markets make analytical control necessary to guarantee the safety of a cosmetic product. However, methodologies for the determination of dyes in cosmetics are scarce with respect to those reported for other cosmetic ingredients such as preservatives or ultraviolet UV ﬁlters. In addition, most of the existing methods just consider a part of the total of dyes regulated. On the other hand, many methods have been developed for matrices different than cosmetics such as foodstuff, beverages or wastewater. The current paper reviews the recent developments in analytical methodologies for the control of synthetic dyes in cosmetics proposed in the international scientiﬁc literature in the last 10 years (2008–2018). A trend towards the use of miniaturized extraction techniques is evidenced. Due to the hydrophilic nature of dyes, liquid chromatography is the most usual choice in combination with absorbance detectors and, more recently, with mass spectrometry.

Keywords: cosmetics; dyes; cosmetics analysis; sample preparation; matrix solid-phase dispersion; miniaturized extraction techniques; liquid chromatography; mass spectrometry; cosmetics safety

1. Introduction Colour is a key property of a product to determine the attractiveness for consumers and, therefore, its successful marketing. Colouring agents can be added to cosmetics in order to colour the product itself or to colour a part of the body (skin, hair, nails or eyelashes). In this latter case, the so-called colour cosmetic is a sector with a strong growth in the industry of cosmetics, given the increasing concern with body image motivated by the popularity of social media [1]. According to their use, cosmetics can be classified as leave-on, those that are in prolonged contact with the skin such as lipstick, cream or body lotion, and rinse-off, those that are removed after application such as shampoo, gel or soap. Colorants can be classified according to their structure, source, colour, solubility and application method [2]. Two main categories are established according to solubility: dyes and pigments. Dyes are synthetic organic compounds that are hydro or oil-soluble and they can be found in cosmetics such as skin care products or toiletries whereas pigments are insoluble, they remain in particulate form, and they are mainly employed in toothpastes or decorative make-up [3]. Among the thousands of substances employed as colouring agents, synthetic dyes are preferred over natural (obtained from plants, animals and minerals) given their lower production costs and long-lasting properties such as brightness or greater stability towards light, heat or pH extreme that may occur during the manufacturing process. They can also be classified according to chemical

Cosmetics 2018, 5, 47; doi:10.3390/cosmetics5030047 www.mdpi.com/journal/cosmetics Cosmetics 2018, 5, 47 2 of 15 structure in five main groups: azoic, triarylmethane, xanthenes, indigoid and quinoline. Table1 shows examples of dyes belonging to each structural family and the corresponding range of Colour Index (CI) number. CI number is a code composed by five numbers used globally to identify these substances. The first two digits indicate the structural category of the dye. Sometimes, they are associated also to an E code, which means that they can be used as food additives. CosmeticsCosmetics 20182018 2018,,, ,55 5,,, ,xxx x FORFORFOR FOR PEERPEERPEER PEER REVIEWREVIEWREVIEW REVIEW 222 ofof of 1717 17 Table 1. Classification of dyes according to their chemical structure. TableTable 1. 1. Classification Classification of of dyes dyes according according to to their their chemical chemical structure. structure.

CategoryCategoryCategory CI RangeCICI Range Range Example Example

AzoAzoAzo 11XXX–35XXX11XXX–35XXX11XXX–35XXX

CICI 19140 19140 Tartrazine Tartrazine

TriarylmethaneTriarylmethaneTriarylmethane 42XXX–44XXX 42XXX–44XXX42XXX–44XXX

CICI 42090 42090 Brilliant Brilliant Blue Blue

XantheneXantheneXanthene 45XXX45XXX45XXX

CICI 45410 45410 Acid Acid Red Red 92 92

QuinolineQuinolineQuinoline 47XXX47XXX47XXX

CICI 47005 47005 Quinoline Quinoline Yellow Yellow

IndigoidIndigoidIndigoidIndigoid 73XXX73XXX73XXX73XXX

CICI 73015 73015 Indigotine Indigotine

AmongAmong the the thousands thousands of of substances substances employedemployed employed asas as colouringcolouring colouring agents,agents, agents, syntheticsynthetic synthetic dyesdyes dyes areare are preferredpreferred preferred Azo dyes, synthesisedoverover natural natural from (obtained (obtained an aromatic from from plants, plants, amine, animals animals are by and and far minerals) minerals) the most given given used their their inlower lower any production production consumer costs costs product and and due to their lower price.long-lastinglong-lastinglong-lasting Their characteristic propertiesproperties properties suchsuch such asas aschromophoric brbr brightnessightnessightness oror or greatergreater greater azo stabilitystability stability group, towardstowards towards under light,light, light, determined heatheat heat oror or pHpH pH extremeextreme extreme conditions thatthat that may occur during the manufacturing process. They can also be classified according to chemical that can take place in intestinalmaymay occuroccur during bacteria,during thethe manufacturing livermanufacturing cells, and process.process. skin TheyThey surface cancan alsoalso micro bebe classifiedclassified flora [4 according],according may be toto reduced chemicalchemical to aromatic amines suspected to cause mutagenic, genotoxic and carcinogenic effects [5]. Although most of epidemiological studies are oriented towards azo dyes, there are also evidences of health risks of other families of colorants. The main route of human exposure to dyes in cosmetics is dermal contact, with special attention to areas close to mucous membranes such as eyes or lips where decorative make-up is daily applied. It has been proven that triarylmethanes are able to enter the blood stream Cosmetics 2018, 5, 47 3 of 15 after systemic absorption [6]. Another study pointed out genotoxic effects caused by the absorption though the skin of Quinoline Yellow [7]. Xanthenes dyes such as Acid Red 92, Erythrosine, or Rose Bengal, which are very popular in cosmetics due to the red shade formed, have been identified as responsible of the formation of rough skin by reacting with proteins on the skin [8]. For other colorants such as Rhodamine B, harmful effects evidenced [9] have led European Union EU authorities to ban the use of these substances in cosmetics. Among substances intended to colour hair, permanent or oxidative hair dyes are widely used, although they are known as strong allergens [10,11] and thus, the analytical control of these substances is a major concern [12]. However, they have not been considered in this review since they present a chemical nature completely different to synthetic dyes and hence other analytical approaches are needed for their determination in hair dyeing formulations [13]. Only synthetic dyes employed as temporary hair dyes have been included in the methodological review. On the other hand, it is worth mentioning that the colouring agents employed in tattoos and permanent make-up (PMU), this last consisting on semi (permanent) tattoos used to resemble make-up. The main components are pigments, though dyes are also employed in small amounts, particularly in the form of lake due to their stability. Over 80% of the colorants used are organic and more than 60% of them are azo-pigments, some of which can release aromatic amines as by-products or impurities from synthesis. Raw colour materials employed for tattoos and PMU are not specifically produced for this application, so their purity is generally low. Aromatic amines, polycyclic aromatic hydrocarbons (PAH) or heavy metals can be present and thus a comprehensive analytical control of ingredients as well as unwanted substances is highly needed. However, the lack of a European regulatory framework and harmonized analytical methodologies developed specifically for tattoos and PMU makes the control of these substances difficult and represents a concern that must be dealt with separately [14]. This paper reviews the analytical methodology and developments for the control of synthetic dyes in cosmetics reported in international scientific journals in the last 10 years (2008–2018). Analytical improvements made on both sample preparation and determination are discussed. Recent contributions in this field tended to the development of methods based on micro-extraction techniques and liquid chromatography coupled to mass spectrometry.

2. Regulatory Overview Dyes are subject to a wide range of regulatory restrictions across countries. These requirements have been exhaustively reviewed by Weisz et al. [15] and Lores et al. [16]. Concerning the use of cosmetics, and consumer products in general, there are three main regulatory authorities: US Food and Drug Administration (FDA) in US, the European Commission (EC) in the European Union (EU), and the Ministry of Health, Labour and Welfare (MHLW) in Japan. They have established positive lists for dyes permitted in cosmetics [15]. Oxidative hair dyes are not considered in this list and the creation of a positive list for this family of ingredients is one of the short- to medium-term objectives of the EU. The European Regulation of Cosmetic Products (EC 1223/2009) [17], in the Annex IV, lays down the rules for the use of dyes in these products. The cosmetic legislation is frequently being updated, hence analytical methodologies must be constantly improved in order to fulfil the regulatory requirements [16]. In this way, there are no official methods for these compounds. Annex IV lists the 150 colouring agents permitted, sorted in increasing order of CI number. Most of them are not subjected to restrictions of maximum concentrations but some of them are limited to be used in determined types of products. For example, a few can be used only in rinse-off products (36 colorants) and others cannot be applied in mucous membranes (19 colorants) or in eye products (four colorants) [16,17]. Japanese and American regulations are more restrictive with respect to the number of colorants permitted (about 83 [18] and 65 [19] compounds respectively). Moreover, in the case of the US, many colorants, mainly synthetic aromatic organic compounds (also called coal-tar dyes) and their lakes, are subjected to batch certification by the FDA [15]. The different regulatory requirements existing among the main authorities of control hinder the commercialization of cosmetics between Cosmetics 2018, 5, 47 4 of 15 these countries and make the development of analytical methodologies for the control of dyes more necessary. Since some compounds permitted by the European Regulation may be banned by the FDA, the importance of methods available for a broad range of colorants that are both permitted and non-permitted must be highlighted.

3. Analytical Methodology Traditionally, reported methods for the determination of dyes focused on food matrices [20–23]. The analytical methodology for cosmetics ingredients regulated in the positive lists according to the European Regulation 1223/2009 [17] was reviewed in 2016 [16]. Thus, this paper only considered permitted dyes, and so, methodologies for the analysis of banned compounds were not included. In the current review, the field has been extended to include analytical methods for both permitted and prohibited dyes in cosmetics, which are summarised in Table2. This table compiles analytical methodologies developed for the determination of synthetic dyes in any kind of cosmetics and reported in international journals between 2008 and 2018. These methodologies are scarce with respect to all those reported for other cosmetic ingredients such as preservatives or UV filters. Moreover, there are no official methods to date in UE, and the existing methods just consider a part of the total regulated dyes. Many methods have also been applied in other matrices such as foodstuff, beverages or wastewater.

Table 2. Analytical methodologies for dyes in cosmetics published in international scientiﬁc literature (2008–2018) (underlined compounds are forbidden according to the European Directive on Cosmetics 1223/2009; abbreviations are listed in AppendixA).

Analyte Sample Matrix Sample Preparation Analysis Year Ref. Lip gloss, lip lacquer, lipstick, body lotion, body butter, hand cream, age CI 14700, CI 14720, CI 15510, CI 15985, Single-step vortex spot corrector mask, rough skin CI 16035, CI 16185, CI 16255, CI 19140, extraction and clean-up remover, shampoo, shower gel, LC-MS/MS 2018 Guerra et al. [24] CI 42051, CI 42090, CI 44090, CI 47005, 1.5 mL of MeOH and 0.1 products combining both, soap, facial CI 60730, CI 73015 g of C18 for clean-up and intimate gels, moisturizing and smoothing masks and toothpaste SPE and CPE Using amberlite as UV-Vis CI 45170 Lipstick adsorbent and surfactant 2018 Bisgin et al. [25] spectroscopy Previous solution in CCl4 CI 13065, CI 14700, CI 14720, CI 15510, Children’s shampoo, children’s Micro-MSPD CI 15985, CI 16035, CI 16185, CI 16255, toothpaste, face painting, lip balm, Using C18 as sorbent CI 19140, CI 42051, CI 42090, CI 42640, LC-MS/MS 2017 Guerra et al. [26] coloured hairspray, eye shadow, soap, and 2 mL of MeOH for CI 44090, CI 45170, CI 45410, CI 45430, nail polish elution CI 47005, CI 60730, CI 73015 DLLME UV-Vis CI 45170 Lipstick, rouge and nail polish THF and decanoic acid 2017 Ozkantar et al. [27] spectroscopy as dispersing solvents MSA-DLLME CI 45160, CI 45170 Lipstick 1-octanol and acetone as HPLC-Vis 2015 Ranjbari et al. [28] dispersing solvents Micro-MSPD CI 14700, CI 15510, CI 15985, CI 16035, Lip balm, nail polish, eye shadow, Using Florisil as sorbent CI 19140, CI 42090, CI 45410, CI 47005, toothpaste, shampoo, decorative LC-MS/MS 2015 Guerra et al. [29] and 2 mL of MeOH for CI 60730 makeup, perfume and mouthwash elution Sample dilution and SPE HPLC-DAD with CI 12245, CI 12250, CI 12719, CI 56059, Semi-permanent hair-dyeing Strata-X cartridges and IL 2015 Franco et al. [30] CI 60730 formulations ACN/H2O (1:1) for Comparison with elution LC-MS/MS CI 11920, CI 12055, CI 12140, CI 26100, OS-AALLME Lipstick HPLC-UV 2015 Barﬁ et al. [31] CI 26105 ILs as extraction solvent CI 10316, CI 14700, CI 14720, CI 15510, CI 15850, CI 15850:1, CI 15880:1, CI 15985, CI 16035, CI 16185, CI 16255, CI 17200, CI 19140, CI 42051, CI 42053, CI Lip product, nail polish, eye product, US and centrifugation Miranda-Bermudez 42090, CI 45100, CI 45170, CI 45350, CI blush, body glitter, face paint, cream Combining DCM, LC-PDA 2014 et al. [32] 45350:1, CI 45370, CI 45380, CI 45380:2, and toothpaste MeOH, HAc and H2O CI 45410, CI 45410:1, CI 45430, CI 47005, CI 59040, CI 60730, CI 61570, CI 73015, CI 75470 CosmeticsCosmetics 20182018, ,55, ,x 47 FOR PEER REVIEW 65 of of 17 15

eye shadow Novel nanocomposite spectroscopy al. [36] as magneticTable 2. sorbentCont.

SPE Analyte Sample Matrix Sample PreparationUV-Vis Analysis YearSoylak Ref. et CI 45170 Lipstick Sepabeads SP 70 resin 2011 US and centrifugation CI 14600, CI 14700, CI 15510, CI 15985, spectroscopy al. [9] and ACN forMeOH-H elutionO for eye CI 16035, CI 16185, CI 16255, CI 18050, Eye shadow, lipstick and lip gloss 2 UPLC-MS/MS 2013 Xian et al. [33] shadow and CHCl -H O CI 19140, CI 20470, CI 42090 3 2 Solvent extractionfor lip products and Voltammetry Nail preparation, Without sample Wang et al. CICI 14700, 15850 CI 15510, CI 15985, CI 26100 Blemish cream and hair dyecentrifugation ComparisonDESI-MS with 2010 2013 Nizzia et al. [34] lipstick and rouge preparation [37] DMF and MeOHIL-DLLME (2:8) LC-UVUV-Vis CI 40290 Eau de toilette and shampoo 2013 Guo et al. [35] Adjusted to pH 4 spectroscopy Micro SPE Solvent extraction in Fluorescence CI 45170 Shampoo, pencil and eye shadow Novel nanocomposite as FIA 2013 Bagheri et al. [36] hot water spectroscopy Wang et al. CI 45170 Lipstick magnetic sorbent Fluorescence 2008 SPE (emulsion for micellar UV-Vis [38] CI 45170 Lipstick Sepabeads SP 70 resin spectroscopy 2011 Soylak et al. [9] spectroscopy determination)and ACN for elution Solvent extraction and Voltammetry CPE CI 15850Hand washing Nail preparation, liquid lipstick and rouge centrifugation UV-VisComparison with 2010Pourreza Wang et al. et [37 ] CI 45170 Aq solution withDMF andTriton MeOH (2:8) LC-UV 2008 soap Solvent extraction in hotspectroscopy al. [39] FIA X-100 in acidicwater media CI 45170 Lipstick Fluorescence 2008 Wang et al. [38] (emulsion for micellar spectroscopy CI 11020, CI 11285, CI determination) CPE 11920, CI 12055, CI UV-Vis CI 45170 Hand washing liquid soap Aq solution with TritonHPLC-UV and 2008 PourrezaNoguerol et al. [39] 12140, CI 26100, CI Commercial products Not provided spectroscopy 2008 X-100 in acidic mediaHPLC-MS/MS et al. [40] CI 11020, CI 11285, CI 11920, CI 12055, 26105, CI 26150, CI HPLC-UV and CI 12140, CI 26100, CI 26105, CI 26150, Commercial products Not provided 2008 Noguerol et al. [40] HPLC-MS/MS CI42000:1, 42000:1, CICI 61554 61554

OutOut of 5454 dyes dyes considered considered in thein papersthe papers reviewed, reviewed, 16 are banned16 are banned according according to European to RegulationEuropean Regulation(colour index (colour underlined index underlined in Table2) andin Table 38 are 2) permitted,and 38 are which permitted, represents which a represents limited share a limited of the sharecolorants of the regulated colorants by regulated Annex IV by [17 Annex]. Figure IV1 [17].shows Figure the 10 1 permittedshows the dyes10 permitted most determined dyes most in determinedcosmetics. in They cosmetics. mainly They correspond mainly to correspond red shades to and red sevenshades of and them seven belong of them to the belong azoic to group. the azoicRegarding group. banned Regarding dyes, banned the majority dyes, the of studies majority are of focused studies on are the focused determination on the determination of Rhodamine of B. RhodamineGiven its genotoxic B. Given effects, its genotoxic many methodseffects, many have methods been exclusively have been developed exclusively for thedeveloped analysis for of the this analysiscompound of this [9,25 compound,27,28,36,38 [9,25,27,28,36,38,39],,39], and it will be commented and it will on be separately. commented With on theseparately. exception With of these the exceptioncases, the of current these trendcases, is the the current development trend ofis methodsthe development for the simultaneous of methods analysisfor the simultaneous of mixtures of analysiscolorants: of mixtures up to 32 forof colorants: qualitative up analysis to 32 for [32 qualitative] or 19 for analysis quantitative [32] or analysis 19 for [quantitative26]. Although analysis out of [26].the periodAlthough considered out of the in period this review, considered it is worthy in this toreview, note that it isin worthy 1997 Rastogi to note etthat al. in [41 1997] built Rastogi a useful et al.spectral [41] built library a useful consisting spectral of library retention consisting times and of retention UV-Vis spectratimes and of 130UV-Vis organic spectra cosmetic of 130 colorants organic cosmeticfor the purpose colorants of for identifying the purpose the of colouring identifying matter the incolouring cosmetic matter products, in cosmetic and a method products, based and ona methodextraction based by SPEon extraction and analysis by bySPE HPLC-DAD and analysis with by ion-pair HPLC-DAD mobile with phase ion-pair was optimized mobile phase for routine was optimizedcontrol of for colorants routine in control lipsticks of andcolorants varnishes. in lipsticks and varnishes.

7 6 5 4 3 2 Nº Publications 1 0 CI 14700 CI 15510 CI 15985 CI 42090 CI 16035 CI 19140 CI 60730 CI 16185 CI 16255 CI 47005 Dyes

Figure 1. Top 10 permitted dyes analysed in cosmetics in the last 10 years (bar colour corresponds with Figure 1. Top 10 permitted dyes analysed in cosmetics in the last 10 years (bar colour corresponds the shade of each dye). with the shade of each dye).

It should also be mentioned that some methods have been reported for the control of impurities and subsidiary compounds in raw material or other contaminants that can be produced during the

Cosmetics 2018, 5, 47 6 of 15

Cosmetics 2018, 5, x FOR PEER REVIEW 7 of 17 It should also be mentioned that some methods have been reported for the control of impurities andmanufacturing subsidiary compoundsprocess [42–45]. in raw Subsidiary material orcolours other contaminantsare a type of thatimpurities can be producedwhich are duringpositional the manufacturingisomers of the processdye anion [42– 45or ].have Subsidiary higher colours or lower are numbers a type of impuritiesof substituen whicht groups are positional [43]. The isomers FDA ofroutinely the dye analyses anion or these have highersubstances or lower in colorants numbers and of substituenttheir lakes groupsto comply [43]. with The FDAthe regulatory routinely analysesspecifications these of substances the batch incertification colorants and program their lakes as was to complymentioned with before. the regulatory From an speciﬁcationsanalytical point of theof view, batch this certiﬁcation complex programmatter requires as was mentioned a different before. methodological From an analytical approach point which of is view, out thisof the complex scope matterof this revision. requires a different methodological approach which is out of the scope of this revision.

3.1. Sample Preparation Cosmetics areare very very different different in their in formtheir (liquid,form (liquid, semisolid, semisolid, powder, wax,powder, etc.) andwax, composition. etc.) and Thecomposition. content ofThe colorants content inof colorants cosmetics in may cosmetics also vary may widely also vary depending widely depending on the type on ofthe product. type of Decorativeproduct. Decorative cosmetics cosmetics such as lipsticks, such as blushes, lipsticks, face blushes, powders, face mascaras, powders, eye mascaras, products eye or nailproducts polishes, or containnail polishes, the highest contain percentage the highest of pe dyes.rcentage Therefore, of dyes. these Therefore, matrices these have matrices been the have subject been of mostthe subject of the analyticalof most of studiesthe analytical [15]. studies [15]. Sample preparation is a necessary step in the analytical process and it often requires time and energy-consuming operations that imply large am amountsounts of organic solvents, acids or chemicals. Currently, the main main priority priority is is the the development development of ofsustainable sustainable methodologies methodologies in accordance in accordance with with the theprinciples principles of green of green chemistry. chemistry. Simple Simple and and rapid rapid methodologies methodologies with with minimal minimal consumption of reagents and solvents are increasinglyincreasingly demandeddemanded by controlcontrol laboratories.laboratories. In recent years, there has been aa tendency tendency towards towards the usethe ofuse microextraction of microextra techniquesction techniques or the miniaturization or the miniaturization of conventional of proceduresconventional of procedures sample preparation. of sample Figure preparation.2 briefs theFigure sample 2 briefs extraction the sample strategies extraction proposed strategies in the methodsproposed summarized in the methods in Table summarized2. The amount in Table and 2. type The of amount solvent and employed type of is solvent an important employed factor is toan developimportant more factor environmental to develop friendlymore environmental alternatives. In fr general,iendly alternatives. methanol or mixturesIn general, of methanolmethanol and or othermixtures polar of solventsmethanol were and preferred other polar as elutingsolvents or were extracting preferred solvent as eluting and in particularor extracting when solvent the extracts and in areparticular subsequently when analysedthe extracts by LC,are givensubsequently its compatibility analysed with by theLC, mobile given phase.its compatibility However, extractionwith the ofmobile dyes fromphase. wax-based However, cosmetics extraction such of asdyes lip productsfrom wax-based often involved cosmetics the usesuch of as toxic lip organicproducts solvents often suchinvolved as chloroform the use of ortoxic dichloromethane. organic solvents such as chloroform or dichloromethane.

Figure 2. Sample extraction strategies for dyes in cosmetics proposed in the international scientific Figure 2. Sample extraction strategies for dyes in cosmetics proposed in the international scientiﬁc literature (2008–2018). literature (2008–2018). Some methodologies focused on the determination of a unique colorant in one or a few cosmeticSome matrices. methodologies In this focusedline, Wang on theet al. determination [37] proposed of a a simple unique sample colorant treatment in one or for a few the cosmeticanalysis matrices.of Lithol Rubine In this line,B (CI Wang 15850) et in al. nail [37 ]preparation, proposed a lipstick simple sampleand rouge, treatment and Guo for et the al. analysis [35] developed of Lithol a Rubinemethod Bbased (CI 15850) on inionic nail liquid preparation, dispersive lipstick liquid-liquid and rouge, andmicroextraction Guo et al. [35 ](IL-DLLME) developed a methodfor the baseddetermination on ionic liquidof Brilliant dispersive Blue (CI liquid-liquid 42090) in microextractioneau de toilette and (IL-DLLME) shampoo. for DLLME the determination is a relatively of recent micro-extraction technique based on a ternary component solvent system. An adequate extraction solvent and disperser solvent are added to the aqueous sample to form a cloudy solution. To collect the enriched phase with the analytes, a solvent with higher density than water must be

Cosmetics 2018, 5, 47 7 of 15

Brilliant Blue (CI 42090) in eau de toilette and shampoo. DLLME is a relatively recent micro-extraction technique based on a ternary component solvent system. An adequate extraction solvent and disperser solvent are added to the aqueous sample to form a cloudy solution. To collect the enriched phase with the analytes, a solvent with higher density than water must be used. The conventional solvents for DLLME are chlorobenzene, chloroform, carbon tetrachloride, and carbon disulfide. The use of ionic liquids (IL), considered more environmentally friendly, improve the sensitivity and selectivity, becoming an interesting approach; however, dispersing solvents, heating and cooling down, ultrasonication or additional chemical reagents are frequently required for the dispersion and sedimentation of ILs, resulting in long sampling time. To avoid these additional requirements, Guo et al. [35] employed 1-decyl-3-methylimidazolium tetrafluoroborate ([C10MIM][BF4]) as the ionic liquid for the sample preconcentration. A full optimization of parameters affecting the micro-extraction such as volume of IL, pH and time of incubation and centrifugation was performed. Since an aqueous media is needed for the dispersion of ILs, this is a selective and sustainable approach only for water soluble samples. As mentioned before, Rhodamine B is a widely considered dye. In recent years, several methods have been developed for its determination in cosmetics, especially in lipsticks. In 2008, Wang et al. [38] proposed a spectrofluorimetric method with minimal pre-treatment based on dissolution of lipstick in hot water by mechanical stirring. Adding an anionic surfactant during the flow-injection analysis increased the fluorescent sensitivity until 2.5 fold. With this procedure, the authors estimated a sampling rate higher than 100 samples h−1. In the same year, Pourreza et al. [39] developed a method based on cloud point extraction using Triton X-100 as non-ionic surfactant in acidic media. This preconcentration and extraction technique is considered in accordance with the “green chemistry” principles. It is based on the separation, at a certain temperature, of two phases in aqueous solution, one of small volume rich in surfactant and another with low concentration. After separation, the turbid solution is cooled down, so the surfactant rich phase becomes viscous and it is easily separated by decantation. The method was applied to different types of samples including a cosmetic one: hand washing liquid soap. Solid phase extraction is a well-established preconcentration method generally applied to the analysis of trace amounts of analytes in environmental samples. It has also been proposed as an alternative extraction technique for lipstick [9,25,36]. Soylak et al. [9] developed a method using SPE with Sepabeads SP 70 resin as adsorbent. The purpose was to preconcentrate traces of Rhodamine B in waste water samples and soft drinks but it was also applied to the extraction of the dye in lipstick, previously dissolved in water by heating and stirring. Rhodamine retained in the adsorbent was eluted with 5 mL of acetonitrile and analysed by UV-Vis spectrophotometer. Validation was performed only for the liquid samples so extraction efficiency in lipsticks is not provided. Rhodamine B was identified and quantified in two lipsticks at concentrations of 39 and 127 µg·g−1. Recently, Bi¸sginet al. [25] developed two extraction methods based on SPE and CPE (cloud point extraction) for the determination of Rhodamine B in lipstick as well. In both cases, sample was previously dissolved in 25 mL of CCl4, which is potentially a long-term carcinogenic solvent. For SPE, amberlite XAD-1180 was used as adsorbent and 5 mL of ethanol to elute Rhodamine. For CPE, Tergitol NP-7 was employed as surfactant. In view of the experimental procedure, SPE implies a shorter sampling time, higher preconcentration factor and better repeatability. On the other hand, sensibility is slightly better in the case of CPE. In 2013, Bagheri et al. [36] synthetized a novel magnetic nanocomposite (Fe3O4–aniline-naphthylamine) as a high-efficient sorbent for micro-SPE for the determination of Rhodamine in several samples including shampoo, eye pencil and eye shadow. In this case, an amount of 7 mg of sorbent is added to the sample solution and stirred for 10 min. Then, the sorbent is collected with an external magnet and Rhodamine is desorbed with 2 mL of methanol. This alternative sorbent led to higher extraction efficiency due to its increased sorbent surface area and porosity. Finally, two methods based on DLLME have been developed for the determination of Rhodamine B in decorative make-up (lipstick, rouge and nail polish) [27] and Rhodamine B and 6G (CI 45160) Cosmetics 2018, 5, 47 8 of 15 in lipstick [28]. The first method [27] is based on the combination of two supramolecular solvents, polar and non-polar, such as THF or decanoic acid. Although the experimental procedure is considered fast, prior to micro-extraction a step consisting of solving 0.5 g of sample in 10 mL of ethyl alcohol and shaking for 2 h is needed. In the second case, Ranjbari and Hadjmohammadi [28] optimized a method based on magnetic stirring assisted DLLME (MSA-DLLME), using 1-octanol and acetone as extraction and dispersing solvent, respectively. As mentioned before, DLLME needs extraction solvents with higher density than water, which frequently implies the use of toxic organic solvents. To overcome this limitation, magnetic stirring is introduced in the methodology in order to help to maintain the cloudy solution and to accelerate the mass transfer from aqueous solution to the extraction solvent, without the need for ultrasonication. A home-made glassware extraction cell has been designed to improve the magnet rotation and to simplify the collection of the supernatant organic solvent enriched with the analytes after centrifugation. To apply a technique based on liquid-liquid extraction to a solid sample such as lipstick, a previous treatment is obviously needed. In this case, 0.05 g of lipstick was solved in 50 mL water assisted by ultrasonic waves and mechanical stirring, and then it was filtered and transferred to the extraction cell. In the context of a growing market of colour cosmetics, multianalyte analytical methodologies are indispensable to satisfy the increased demand of quality control. In the period under consideration, the first extraction method for the determination of a mixture of dyes was proposed by Xian et al. [33] in 2013. Before this work, several multianalyte methods are worthy to consider. Noguerol et al. [40] developed a method based on HPLC-UV and HPLC-ESI-MS/MS for the application to commercial products, but neither the type of sample nor sample preparation method were provided. Nizzia et al. [34] proposed an analytical approach based on desorption electrospray ionization mass spectrometry (DESI-MS), where sample treatment is not required for the analysis. The work published by Xian et al. [33] was focused on the development of a method for the analysis of 11 dyes in cosmetics. In this way, a simple methodology based on vortexing, ultrasounds and centrifugation was successfully applied achieving quantitative recoveries in eye shadow, lipstick and lip gloss. However, for the extraction from waxy matrices, longer sampling time and chlorinated solvents were required though in small volumes (2 mL of chloroform). Similar liquid-liquid extraction using combinations of dichloromethane, methanol, acetic acid and water, was proposed by Miranda-Bermudez et al. [32]. The developed and validated methodology was employed to survey 29 colour additives, including water and methanol-soluble permitted dyes and the most prevalent non-permitted colour additives found by FDA’s district laboratories, in 38 samples of lip and eye products, nail polish, blush, body glitter, face paint, cream and toothpaste. Despite the broad range of analytes and samples studied, this methodology was developed only for the qualitative identification of dyes. Barfi et al. [31] and Franco et al. [30] focused mainly on the determination of illegal dyes in cosmetics. In the first work, a novel, simple and eco-friendly method based on one step air-assisted liquid-liquid micro-extraction (OS-AALLME) was developed to extract Sudan dyes and Orange G in lipstick. In addition, because of the high risk of direct oral ingestion of sample, the validated extraction method was applied to estimate the concentration of a potential biomarker of these dyes, 1-amino-2-naphthol, in human bio-fluids. The advantage of this approach is the application of ILs as extraction solvent, avoiding the use of organic solvent. The immiscibility of ILs in water and their capability to solubilize organic species make them a valuable alternative to conventional solvents. To carry out the dispersion of the IL in aqueous solution, the mixture is repeatedly withdrawn into a glass syringe and pushed out (AALLME), while sonication is performed in order to increase the surface contact between the immiscible liquids and then, to enhance the extraction efficiency. In this way, micro-extraction takes place in one step. On the other hand, Franco et al. [30] developed a method based on sample dilution in water and SPE for the determination of four basic dyes and one acid dye used as semi-permanent hair colorants. Oxidative hair dyes have been the subject of most of the analytical methodologies for the control of hair colorants due to their widespread use and there Cosmetics 2018, 5, 47 9 of 15 are very few methods for semi-permanent dyes. Hair dyeing formulations do not require a complex extraction method. After shampooing, the dyes are retained in the structure of hair through ionic interactions or van der Waal forces. Recently, Guerra et al. have been working on improving the simultaneous analysis of a great number of chemically different dyes in a broad range of cosmetics, including rinse-off and leave-on Cosmeticsproducts 2018 [24, 5,26, x ,FOR29]. PEER In 2015 REVIEW [29], they introduced the matrix solid-phase dispersion (MSPD) for10 of the 17 first time in the analysis of dyes in cosmetics. MSPD is a valuable approach for solid and semisolid samples forfor itsits simplicitysimplicity and and the the possibility possibility of of performing performing a clean-up a clean-up step step simultaneously. simultaneously. In this In case,this case,miniaturization miniaturization of the of conventional the conventional procedure procedur employinge employing a Pasteur a Pasteur pipette pipette as device as indevice order in to order pack tothe pack sample the dispersedsample dispersed (see Figure (see3), Figure allowed 3), extracting allowed extracting quantitatively quantitatively nine dyes nine in many dyes cosmetics in many cosmeticsincluding including lipstick, nail lipstick, polish nail or toothpaste.polish or toothpaste. More recently, More they recently, published they published a new method a new [26 method] based [26]on miniaturized based on miniaturized MSPD with MSPD significant with significant improvements improvements in relation in to relation the previous to the one. previous In this one. work, In 19this permitted work, 19 andpermitted banned and dyes banned were dyes analysed, were analys 10 moreed, than10 more in the than former, in the in former, a broader in a rangebroader of rangematrices, of matrices, which involved which ainvolved re-optimization a re-optimization of the sample of preparationthe sample procedurepreparation using procedure experimental using experimentaldesigns. The Pasteurdesigns. pipette The Pasteur was replaced pipette bywas a 2repl mLaced syringe by a to2 enablemL syringe an adequate to enable solvent an adequate elution solventemploying elution the dispersantemploying chosen the dispersant as the optimum, chosen as C18. the The optimum, most recent C18. multi-dyeThe most methodrecent multi-dye was also methodreported was by Guerra also reported et al. [24 by]. Single-step Guerra et vortexal. [24] extraction. Single-step and vortex simultaneous extraction clean-up and simultaneous was applied clean-upto the analysis was applied of dyes to as the well analysis as preservatives of dyes as inwell different as preservatives cosmetics, in many different of whom cosmetics, have notmany been of whomanalysed have yet. not In been comparison analysed with yet. other In comparison approaches with based other on simpleapproaches solvent based extraction on simple assisted solvent by extractionultrasounds assisted or centrifugation, by ultrasounds this methodor centrifugati offerson, advantages this method in terms offers of advantages simplicity, rapidityin terms and of simplicity,minimal consumption rapidity and of minimal solvents. co Innsumption addition, itof may solvents. be considered In addition, more it environmentallymay be considered friendly more environmentallysince it avoids the friendly use of solvents since it avoids such as the dichloromethane use of solvents orsuch chloroform. as dichloromethane or chloroform.

Figure 3. Miniaturized matrix solid-phase dispersion (MSPD) procedure. Figure 3. Miniaturized matrix solid-phase dispersion (MSPD) procedure.

3.2. Analytical Techniques 3.2. Analytical Techniques In order to identify and quantify properly the dyes in cosmetic samples, a chromatographic In order to identify and quantify properly the dyes in cosmetic samples, a chromatographic separation is frequently required. Liquid chromatography coupled to absorbance or mass separation is frequently required. Liquid chromatography coupled to absorbance or mass spectrometry spectrometry detectors were proposed in all analytical methodologies for the simultaneous detectors were proposed in all analytical methodologies for the simultaneous determination of mixtures determination of mixtures of dyes (Table 3). Due to the capability of dyes to absorb in the UV-Vis of dyes (Table3). Due to the capability of dyes to absorb in the UV-Vis spectrum, DAD or UV-Vis spectrum, DAD or UV-Vis detectors were traditionally the preferred detectors [28,30–32]. In recent detectors were traditionally the preferred detectors [28,30–32]. In recent years, mass spectrometry has years, mass spectrometry has become a valuable choice [24,26,29,33,34], given its enhanced become a valuable choice [24,26,29,33,34], given its enhanced selectivity and sensitivity; it is particularly selectivity and sensitivity; it is particularly desired in the analysis of banned compounds. Mass desired in the analysis of banned compounds. Mass spectrometry overcomes limitations of DAD such spectrometry overcomes limitations of DAD such as overlapping of UV-Vis spectra among matrix ingredients. In some studies, a comparison between LC-DAD and LC-MS/MS was established [30,40]. In this way, Noguerol et al. [40] developed two LC methods with UV-Vis detection and with tandem mass spectrometry triple quadrupole in positive ion mode electrospray ionization (ESI) for the routine control of 10 dyes, mainly dyes banned in cosmetics. LC-ESI-MS/MS in full scan mass spectra mode allowed to obtain structural information about multiple peaks observed for some of the studied dyes through HPLC-UV/Vis analysis. The presence of more than one peak for a compound was mainly due to possible isomerization processes, impurities or degradation products. In addition, multiple reaction monitoring (MRM) mode was employed for quantification purposes.

Cosmetics 2018, 5, 47 10 of 15 as overlapping of UV-Vis spectra among matrix ingredients. In some studies, a comparison between LC-DAD and LC-MS/MS was established [30,40]. In this way, Noguerol et al. [40] developed two LC methods with UV-Vis detection and with tandem mass spectrometry triple quadrupole in positive ion mode electrospray ionization (ESI) for the routine control of 10 dyes, mainly dyes banned in cosmetics. LC-ESI-MS/MS in full scan mass spectra mode allowed to obtain structural information about multiple peaks observed for some of the studied dyes through HPLC-UV/Vis analysis. The presence of more than one peak for a compound was mainly due to possible isomerization processes, impurities or degradation products. In addition, multiple reaction monitoring (MRM) mode was employed for quantification purposes. In terms of sensitivity, there was a remarkable difference between both methods. Limits of quantification were one or two orders of magnitude lower for the LC-MS/MS analysis, which is particularly valued given the high restriction of those target dyes in the commercial products. This work focused on the development of an analytical method for its implementation in the control of dyes in commercial products, but not specifically for cosmetics.

Table 3. Performance of analytical methodologies for multi-dye determination in cosmetics (2008–2018).

Dye Recovery (%) LOD/LOQ RSD (%) Ref. Liquid Chromatography Coupled to Mass Spectrometry CI 14700, CI 14720, CI 15510, CI 15985, CI 70.3–117 –/0.070–3.437 µg g−1 <13 Guerra et al. [24] 16035, CI 16185, CI 16255, CI 19140, CI 42051, CI 42090, CI 44090, CI 47005, CI 60730, CI 73015 CI 13065, CI 14700, CI 14720, CI 15510, CI 69.5–121 0.0142–0.476 µg·g−1/– <15 Guerra et al. [26] 15985, CI 16035, CI 16185, CI 16255, CI 19140, CI 42051, CI 42090, CI 42640, CI 44090, CI 45170, CI 45410, CI 45430, CI 47005, CI 60730 CI 73015 CI 14700, CI 15510, CI 15985, CI 16035, CI 70–120 0.010–0.62/1–5 ng·mL−1 (LLOQ) <15 Guerra et al. [29] 19140, CI 42090, CI 45410, CI 47005, CI 60730 CI 14600, CI 14700, CI 15510, CI 15985, CI 81.6–118.2 1.2–30.3/4.1–100 µg·kg−1 <8 Xian et al. [33] 16035, CI 16185, CI 16255, CI 18050, CI 19140, CI 20470, CI 42090 CI 11020, CI 11285, CI 11920, CI 12055, Not provided 4.54–14.3/15.0–47.6 µg·L−1 – Noguerol et al. [40] CI 12140, CI 26100, CI 26105, CI 26150, CI 42000:1, CI 61554 Liquid Chromatography Coupled to Absorbance Detector CI 45160, CI 45170 97–100 1.15–1.23/3.82–4.10 ng·mL−1 <2 Ranjbari et al. [28] CI 12245, CI 12250, CI 12719, CI 56059, CI Not provided 0.53–2.98 × 10−7/ 1.08–3.66 × 10−7 <5 Franco et al. [30] 60730 mol·L−1 CI 11920, CI 12055, CI 12140, CI 26100, 86.8–102.3 3.9–84.8 ng·mL−1/– <6 Barﬁ et al. [31] CI 26105 CI 10316, CI 14700, CI 14720, CI 15510, CI – 0.1–1.5 mg·L−1 (estimated, qualitative – Miranda- Bermudez 15850, CI 15850:1, CI 15880:1, CI 15985, CI method)/– et al. [32] 16035, CI 16185, CI 16255, CI 17200, CI 19140, CI 42051, CI 42053, CI 42090, CI 45100, CI 45170, CI 45350, CI 45350:1, CI 45370, CI 45380, CI 45380:2, CI 45410, CI 45410:1, CI 45430, CI 47005, CI 59040, CI 60730, CI 61570, CI 73015, CI 75470 CI 11020, CI 11285, CI 11920, CI 12055, Not provided 60–890/200–2990 µg·L−1 – Noguerol et al. [40] CI 12140, CI 26100, CI 26105, CI 26150, CI 42000:1, CI 61554 DESI-MS CI 14700, CI 15510, CI 15985, CI 26100 – 15–100 ng 9–27 Nizzia et al. [34] (<1 ng SRM mode)

The combination of liquid chromatography and mass spectrometry in the analysis of dyes in cosmetics was reported for the ﬁrst time by Xian et al. [33] in 2013. Afterwards, Guerra et al. developed several improved methods based on this analytical technique [24,26,29]. Most of the dyes used in cosmetics and so considered in this review are sodium or calcium salts which contain in their structures one or more ionized groups such as sulphonic groups. This fact implies the possible formation of multicharged ions in the ionization source. In addition, the separation of ionic compounds by reverse phase liquid chromatography is a challenging task and more efforts must be done in relation to the separation of neutral compounds. In this respect, the mobile phase (ionic strength, pH, and composition) plays an important role. In some cases, a mobile phase without additives, composed by water and an organic modiﬁer (acetonitrile or methanol), has been employed achieving good sensitivity and a fast analysis [29,33]. The use of UPLC allowed performing the analysis of Cosmetics 2018, 5, 47 11 of 15

11 dyes in 4 min [33]. Similar results were achieved for a mixture of nine dyes with a conventional porous C18 column [29]. Although the use of mass spectrometry allows a selective identification of co-eluted compounds, a chromatographic separation is generally recommended. For this purpose, the addition of volatile neutral salts to mobile phase is necessary in order to avoid interactions between ionized negatively charged compounds and partially ionized residual silanols in the stationary phase [46]. However, the presence of salts in the ion source may cause a suppression of the ionization. Thus, the composition of mobile phase must be investigated to achieve a compromise between good separation and performance. In this way, the use of only 3 mM ammonium acetate in the aqueous mobile phase was proposed [24,26]. This salt concentration was enough to avoid peak tailing while improving the chromatographic separation for quite a number of analytes with satisfactory limits of quantification. In the most recent work [24], other chromatographic parameters were optimized to separate dyes and preservatives. The matrix effect is the ionization suppression or enhancement of the target compound by others present in the sample and it is very frequent in LC-MS/MS analysis, in particular when electrospray sources are used. In every method for dyes analysis using MS/MS detector, a study of matrix effect was performed. The most comprehensive study was carried out for 19 dyes in seven cosmetic matrices (lip balm, nail polish, hairspray, eye shadow, toothpaste, face painting and gel) [26]. In all cases, the optimized sample extraction procedure allowed obtaining an extract clean enough to perform the analysis with negligible matrix effects, with particular exceptions for some compounds in very few matrices. In contrast to conventional mass spectrometry techniques, Nizzia et al. [34] investigated the use of DESI-MS for the analysis of common semi-permanent hair colorants in two semisolid cosmetic formulations: a blemish cream and a hair-dye gel. As a novelty, the use of an ambient MS technique allowed a direct analysis without prior sample preparation or chromatographic separation. A thin layer of sample is deposited onto porous Teflon and a pneumatically assisted electrospray is employed to release neutral analytes present on this surface as secondary ions. On the other hand, UV-Vis and DAD detectors are still often used in the literature for the analysis of dyes in commercial products. Concerning cosmetics, there have been several methods reported in the last 10 years that combine LC and DAD for the quantitative [28,30–32] and qualitative [32] analysis of multiple dyes or that apply direct spectrophotometric measurement when only one dye is considered [9,25,27,35,39] (see Table4). In these latter methods, good limits of detection were obtained because of the concentration achieved using an extraction technique such as SPE, CPE or DLLME previous to the analysis. Most of these methods were developed to identify and quantify Rhodamine B, so they established a fixed wavelength, 556 nm, which corresponds with the maximum of absorbance of this compound. When a mixture of dyes is analysed, DAD is a useful tool that allows the simultaneous recording of absorbance data from 190 to 800 nm and to match the UV-Vis spectra obtained with spectral libraries.

Table 4. Performance of analytical methodologies for only one dye determination in cosmetics (2008–2018).

Dye Recovery (%) LOD/LOQ RSD (%) Ref. UV-Vis spectroscopy CI 45170 85–100 0.7/1.9 µg·L−1 for CPE, 1.2/3.2 µg·L−1 for SPE <7 Bisgin et al. [25] CI 45170 99–104 0.49/1.47 µg·L−1/ <6 Ozkantar et al. [27] CI 42090 99–103 0.34 µg·L−1 <1 Guo et al. [35] CI 45170 Not provided Not provided <5 Soylak et al. [9] CI 45170 97–102 1.3 ng·mL−1/– <3 Pourreza et al. [39] Fluorescence spectroscopy CI 45170 94–99 0.10/0.35 µg·L−1 <8 Bagheri et al. [36] CI 45170 98–102.4 5 × 10−10/1.6 × 10−9 mol·L−1 <3 Wang et al. [38] Voltammetry CI 15850 Not provided Not provided <4 Wang et al. [37] Cosmetics 2018, 5, 47 12 of 15

For the determination of basic dyes through LC-DAD, Franco et al. [30] proposed the use of ILs in the mobile phase to enhance peak shapes and to reduce the chromatographic retention times. ILs usually compete with basic groups for the residual silanols on the stationary phase or they can form an ion pair with cationic solutes to improve the shielding efficiency of these silanols. In this way, the analysis was completed in 40 min using an isocratic mode with a mobile phase composed by −1 acetonitrile and water and 2 mL of 0.040 mol·L BMIm[NTf2] solution. The results obtained were compared with those obtained though LC-MS/MS by means of a t-student test. Concentration values obtained in both cases were not significantly different (at 95% confidence level). However, it must be pointed out that the mass spectrum provided chemical structural data that were employed to confirm the presence of the target compounds in the hair-dyeing formulations found by LC-DAD analysis. Other analytical approaches were reported based on fluorescence measurements [36,38] or voltammetry [37] for the determination of Rhodamine B or Lithol Rubine, respectively. The main advantage of the fluorometric measurement is its high selectivity.

4. Conclusions Colour increases the marketing success of the consumer products including cosmetics. Synthetic dyes are preferred, particularly azo dyes, even though several studies have evidenced harmful health effects. There are different regulatory requirements for the use of dyes in cosmetics among the main markets (US, Europe and Japan), which becomes a handicap for the commercialization of a specific product. In the EU, with a powerful cosmetic industry, there are not official methods for the determination of synthetic dyes in cosmetics. The present review of analytical methodologies published in international scientific journals in the last 10 years revealed the lack of methods for the simultaneous analysis of multiple dyes. In addition, the range of coloured compounds analysed is very short in comparison with the total of regulated dyes that can be used in personal care products of daily use. Regarding sample preparation, there is a trend towards the micro-extraction techniques. The low consumption of solvents and reagents make them a valuable choice. For the analysis, liquid chromatography is by far the most preferred separation technique. Since most of synthetic dyes are ionized compounds, special efforts should be made for the optimization of the chromatographic separations. Absorbance detectors are a common approach to be considered, but mass spectrometry brings a significant added value in terms of sensitivity and selectivity, especially for the analysis of banned dyes.

Author Contributions: All authors (E.G., M.L., C.G.-J.) conceived and designed the review; E.G. wrote the paper; and M.L. and C.G.-J. supervised the paper. Funding: This research was supported by European Reg. Development Fund (ERDF) (2007–2013), and projects CTQ2013-46545-P (Ministry of Economy and Competitiveness), and GPC2017/04 (Xunta de Galicia). Acknowledgments: E.G. acknowledges Xunta de Galicia for her predoctoral contract and the Ministry of Education, Culture and Sport for an FPU grant. Conﬂicts of Interest: The authors declare no conﬂict of interest.

Appendix A : Abbreviations

ACN acetonitrile CI colour index CPE cloud point extraction DAD diodo-array detector DCM dichloromethane DESI-MS desorption electrospray ionization mass spectrometry DLLME dispersive liquid-liquid microextraction DMF dimethylformamide Cosmetics 2018, 5, 47 13 of 15

ESI electrospray ionization FIA ﬂow injection analysis HAc acetic acid IL ionic liquid IL-DLLME ionic liquid independent disperse liquid-liquid microextraction LLOQ lower limit of quantiﬁcation LPME liquid-phase microextraction MeOH methanol MRM multiple reaction monitoring MSA-DLLME magnetic stirring assisted dispersive liquid-liquid microextraction MSPD matrix solid-phase dispersion OS-AALLME one-step air-assisted liquid-liquid microextraction RSD relative standard deviation SPE solid phase extraction SRM selected reaction monitoring THF tetrahydrofuran UPLC ultra performance liquid chromatography US ultrasounds

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